Molecular and functional investigation of the DUSP12-HP1BP3 proteins interaction in human tumor cells

Abstract

The human genome expresses about 100 functional tyrosine phosphatase enzymes (PTKs) that preferentially dephosphorylate tyrosine residues - but also tyrosine/serine or tyrosine/threonine - phosphorylated on protein substrates and other phospho-biomolecules. Some members of this class have increased protein expression levels in certain types of human tumors such as mammary, cervical, colorectal, pulmonary, pancreatic, hepatic, and gastric. Several experimental pieces of evidence show that some of these enzymes can act in the direct or indirect regulation of mechanisms of maintenance of genomic stability such as cell cycle, DNA repair, chromatin organization, gene expression, and even nuclear architecture, which are essential in the transformation and/or tumor resistance. Our group previously worked on the identification of protein partners of dual-specificity tyrosine phosphatase 12 - DUSP12, also known as YVH1 - in cell lines of breast and lung adenocarcinomas subjected to different types of oxidative and genotoxic stress, and managed to identify important nuclear targets of DUSP12, such as the HP1BP3 protein, which has functions related to chromatin remodeling. This project aims to investigate molecular details of the interaction between DUSP12 and HP1BP3 proteins and its relevance in nuclear processes involved with the malignancy of certain tumor cells and, consequently, to be able to point out functional relationships between it and mechanisms of genomic stability and chromatin reorganization. A greater understanding of the biological mechanisms of action of DUSP12 can identify potential relationships with cellular disorders and, knowing better the interactions underlying the pathological process, suggest therapies that interfere with the activity of this phosphatase whose potential as a clinical drug target is still an open window of therapeutic opportunities. (AU)